Deregulated expression of the c-Myc protooncogene is a frequent requisite for the development of many human cancers. Despite extensive knowledge of its biology, we are still unaware of the precise molecular mechanisms that sustain its oncogenic activity. Amplification of the physiologic control of DNA replication initiation by Myc upon deregulation of its expression in primary cells and transgenic mouse B-cells causes replication stress and subsequent DNA damage. Replication stress is a phenomenon often seen in early cancers from different tissue origin, and it is believed to be consequent to oncogene activation. However, formal proof for its requirement during tumorigenesis is yet to be obtained. The long-term goal of this project is to characterize the contribution of Myc-dependent replication stress to B-cell lymphomagenesis. We will specifically assess whether altering Myc's ability to promote replication stress - by either ablating its ability to control DNA replication or modifying the cellular responses to Myc- dependent replication stress- determines the outcome of the oncogenic process. We hypothesize that pathways coping with replication stress restrain tumor initiation driven by this protooncogene and hence, manipulation of these pathways will determine Myc's ability to generate lymphomas when deregulated in B-cells. This Research Plan is meant to be part of a Career Development Plan through which I aim to obtain critical knowledge and technical skills on: (1) the application of mouse models to the study cancer initiation and progression;and (2) the use of high- throughput technologies and Systems Biology to address general questions in the cancer field that, due to their complexity, require integrated approaches. The extraordinary characteristics of the host center, where all these disciplines are integrated for the study of cancer, ensure an optimal environment for the training period. The mentored phase will therefore allow me to transit with success to an independent phase, where to continue to develop the final parts of this research project, obtain proof of principle for the above proposed research hypothesis, and pursue the study of the basic mechanisms of Myc-dependent B-cell lymphomagenesis, with aim to find novel therapeutic targets for this group of diseases. PUBLIC HEALTH RELEVANCE: Loss of normal control of Myc protein activity occurs in more than 70% of human cancers, and is essential for their initiation, growth and progression. This project proposes to examine the requirement during tumor development of a novel mechanism used by Myc to control cellular proliferation. Confirmation of this requirement will point to this function as a potential novel therapeutic target in a majority of cancer types.